CORE D: Animal Models and In Vivo Evaluation Core

In vivo efficacy testing is essential for the down-selection, evaluation, and development of potent and effective medical countermeasures (MCMs), especially given that many aspects of viral replication and pathogenesis cannot be faithfully recapitulated in vitro. Core D is responsible for providing PROVIDENT Research Projects 1, 2, 3, and 4 animal model testing support required for the validation of newly identified host factors (Project 1; P1) and novel MCMs (Project 2-4; P2-4) against hantaviruses, nairoviruses, and paramyxoviruses. First, we will test in vitro down- selected candidates against family-specific prototype viruses, Andes virus (ANDV), Crimean Congo Hemorrhagic fever virus (CCHFV), and Menangle virus (MenPV), respectively. To meet these objectives, animal models will be developed when unavailable and used in conjunction with widely accepted models. Following, PROVIDENT products will be sprint tested against outgroup hanta-, nairo-, and paramyxo-viruses, Sin Nombre virus (SNV) or Hantaan virus (HTNV), Hazara virus (HAZV), and Nipah virus (NiV), respectively. Core D will also support the development of animal-based tools, including genome-edited murine and Syrian hamsters that will be used to generate novel rodent models of disease and interrogate fundamental viral-host factor interactions. In collaboration with P2, P3, Core C, and Core E, Core D will also assist in the generation of camelid variable heavy chain only antibodies (VHHs), through alpaca immunizations with RNA/NLP and protein immunogens. These nanobodies will serve as important tools to identify critical functional surfaces in viral proteins that can inform immunogen engineering. In addition to animal model development and rodent efficacy studies, Core D will support immunogenicity testing in non-human primates to assess lead mRNA vaccine candidates and provide supporting data for pre-clinical or phase I trials. In sum, the support and scientific rigor provided by Core D will enable PROVIDENT to identify, develop, and test robust MCM against hantaviruses, nairoviruses, and paramyxoviruses in service of the grand goal of developing comprehensive vaccine and therapeutic antibody blueprints against these emerging RNA viruses.